Trandolapril

Drug Interactions Trandolapril did not affect the plasma concentration (pre-dose and 2 hours post-dose) of oral digoxin (0.25 mg). Coadministration of trandolapril and cimetidine led to an increase of about 44% in C max for trandolapril, but no difference in the pharmacokinetics of trandolaprilat or in ACE inhibition. Coadministration of trandolapril and furosemide led to an increase of about 25% in the renal clearance of trandolaprilat, but no effect was seen on the pharmacokinetics of furosemide or trandolaprilat or on ACE inhibition.

Drug Interactions Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on trandolapril tablets and other agents that affect the RAS.

Do not co-administer aliskiren with trandolapril tablets in patients with diabetes. Avoid use of aliskiren with trandolapril tablets in patients with renal impairment (GFR <60 mL/min). Concomitant Diuretic Therapy As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may experience an excessive reduction of blood pressure after initiation of therapy with trandolapril tablets. The possibility of exacerbation of hypotensive effects with trandolapril tablets may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with trandolapril tablets.

If it is not possible to discontinue the diuretic, the starting dose of trandolapril should be reduced. (see DOSAGE AND ADMINISTRATION .) Agents Increasing Serum Potassium Trandolapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Use of potassium-sparing diuretics (spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium.

(see PRECAUTIONS .) Antidiabetic Agents Concomitant use of ACE inhibitors and antidiabetic medicines (insulin or oral hypoglycemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycemia. Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including trandolapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving trandolapril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including trandolapril may be attenuated by NSAIDs.

Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including trandolapril tablets. Mammalian Target of Rapamycin (mTOR) Inhibitors Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema ( see WARNINGS – Head and Neck Angioedema ). Neprilysin Inhibitor Patients taking concomitant neprilysin inhibitors (e.g., sacubitril) may be at increased risk for angioedema (see WARNINGS ).

Other No clinically significant pharmacokinetic interaction has been found between trandolaprilat and food, cimetidine, digoxin, or furosemide. The anticoagulant effect of warfarin was not significantly changed by trandolapril. The hypotensive effect of certain inhalation anesthetics may be enhanced by ACE inhibitors including trandolapril. (see PRECAUTIONS -Surgery/Anesthesia.) Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies were conducted with oral trandolapril administered by gavage to mice (78 weeks) and rats (104 and 106 weeks).

No evidence of carcinogenic potential was seen in mice dosed up to 25 mg/kg/day (85 mg/m 2 /day) or rats dosed up to 8 mg/kg/day (60 mg/m 2 /day). These doses are 313 and 32 times (mice), and 100 and 23 times (rats) the maximum recommended human daily dose (MRHDD) of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg individual. The genotoxic potential of trandolapril was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. There was no evidence of mutagenic or clastogenic potential in these in vitro and in vivo assays.

Reproduction studies in rats did not show any impairment of fertility at doses up to 100 mg/kg/day (710 mg/m 2 /day) of trandolapril, or 1250 and 260 times the MRHDD on the basis of body-weight and body-surface-area, respectively. Nursing Mothers Radiolabeled trandolapril or its metabolites are secreted in rat milk. Trandolapril tablets should not be administered to nursing mothers. Geriatric Use In placebo-controlled studies of trandolapril tablets, 31.1% of patients were 60 years and older, 20.1% were 65 years and older, and 2.3% were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients.

(Greater sensitivity of some older individual patients cannot be ruled out). Pediatric Use Neonates with a history of in utero exposure to trandolapril tablets: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. The safety and effectiveness of trandolapril tablets in pediatric patients have not been established.

Pregnancy Female patients of childbearing age should be told about the consequences of exposure to trandolapril tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. NOTE : As with many other drugs, certain advice to patients being treated with trandolapril tablets are warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.